The ontogeny of fairness in seven societies.

A sense of fairness plays a critical role in supporting human cooperation. Adult norms of fair resource sharing vary widely across societies, suggesting that culture shapes the acquisition of fairness behaviour during childhood. Here we examine how fairness behaviour develops in children from seven diverse societies, testing children from 4 to 15 years of age (n = 866 pairs) in a standardized resource decision task. We measured two key aspects of fairness decisions: disadvantageous inequity aversion (peer receives more than self) and advantageous inequity aversion (self receives more than a peer). We show that disadvantageous inequity aversion emerged across all populations by middle childhood. By contrast, advantageous inequity aversion was more variable, emerging in three populations and only later in development. We discuss these findings in relation to questions about the universality and cultural specificity of human fairness.

Pulsed brachytherapy: a modelled consideration of repair parameter uncertainties and their influence on treatment duration extension and daytime-only "block-schemes".

OBJECTIVES: The radiobiological modelling of all types of protracted brachytherapy is susceptible to uncertainties in the values of tissue repair parameters. Although this effect has been explored for many aspects of pulsed brachytherapy (PB), it is usually considered within the constraint of a fixed brachytherapy treatment time. Here the impact of repair parameter uncertainty is assessed for PB treatments of variable duration. The potential use of "block-schemes" (blocks of PB pulses separated by night-time gaps) is also investigated. METHODS: PB schedule constraints are based on the cervical cancer protocols of the Royal Marsden Hospital (RMH), but the methodology is applicable to any combination of starting schedule and treatment constraint. Calculations are performed using the biologically effective dose (BED) as a tissue-specific comparison metric. The ratio of normal tissue BED to tumour BED is considered for PB regimens with varying total pulse numbers and/or "block-schemes". RESULTS: For matched brachytherapy duration, PB has a good "window of opportunity" relative to the existing RMH continuous low dose rate (CLDR) practice for all modelled repair half-times. The most clear-cut route to radiobiological optimisation of PB is via modest temporal extension of the PB regimen relative to the CLDR reference. This option may be practicable for those centres with scope to extend their relatively short CLDR treatment durations. CONCLUSION: Although daytime-only "block-scheme" PB for cervical cancer has not yet been employed clinically, the possibilities appear to be theoretically promising, providing the overall (external beam plus brachytherapy) treatment duration is not extended relative to current practice, such that additional tumour repopulation becomes a concern.

High dose rate brachytherapy practice for the treatment of gynaecological cancers in the UK.

A summary of UK high dose rate brachytherapy practice in gynaecological cancer is presented. There appears to be relatively good uniformity in dose prescription and biological effective doses, which represents a considerable improvement from the findings of a previous report of UK low dose rate brachytherapy practice in 1991. Individual details of the dose schedules used at each treatment centre are presented.

60 Gy isodose volumes in carcinoma of the cervix and their relation to the geometry of uterine tube and ovoids.

The International Commission on Radiation Units and Measurements recommends the use of 60 Gy isodose volumes for reporting doses in the intracavity treatment of carcinoma of the uterine cervix. This study was aimed at determining the variation in isodose volumes while using different sizes of intrauterine tubes and ovoids, with different applicator geometries. It was based on the treatment plans of 175 patients with cervical cancer, treated with low dose rate intracavitary brachytherapy with or without additional external beam radiotherapy. The volumes encompassed by the 60 Gy isodose curves were calculated using the Nucletron planning system. Applicator positions in 15 patients who were treated to the same point A dose, using 6 cm intrauterine tube and medium ovoids, were recorded. This was to discover how variations in applicator geometry influences isodose volumes. The 60 Gy isodose volumes increased with increasing point A dose. For a constant point A dose prescription, reference isodose volume increased with ovoid applicator size used, but showed no consistent variation with the length of intrauterine tube. There were individual variations in the isodose volumes within a standard set-up (same sized intrauterine tube and ovoids and same point A dose), due to variations in applicator geometry. Displacement of the ovoids changed the volumes encompassed by the reference isodose. There are significant variations in the volumes encompassed by the 60 Gy isodose during intracavitary treatment using a standard set-up, while treatment using applicators of different sizes can give equivalent values of 60 Gy isodose volume. 60 Gy isodose volumes may hence be useful in dosimetric comparisons but have a limited role in predicting clinical response.

Palliative chemotherapy in recurrent carcinoma of the cervix: an audit of the use of ifosfamide and review of the literature.

A review was conducted on 34 patients treated with intravenous ifosfamide for relapsed, inoperable carcinoma of the cervix between 1988 and 1996. The median age of patients was 44 years. Thirty-two patients had squamous cell carcinoma and 2 had adenocarcinoma. Radiotherapy had been used in primary management in 33, neo-adjuvant platinum chemotherapy in 7, and previous palliative chemotherapy in 11. Symptomatic response was assessed with respect to the symptom requiring palliaton. 25 patients failed to complete 6 cycles of chemotherapy: due to progressive disease in 14, lack of symptom response in 2, and toxicity in 11 of whom 7 had encephalopathy sufficient to abandon treatment. 32 patients were evaluable for objective response. Pathologic complete response (CR) was achieved in 1 patient, and partial response (PR) was achieved in 3 patients. The objective response rate was 11.8%. Symptomatic response throughout treatment occurred in 8 patients (24%); objective response was seen in only 3 (1 CR, 2 PR) of them and progressive disease in the remaining 5. Response duration in the 4 objective responders was 25 months in the patient with CR and 4, 6 and 8 weeks in the 3 patients with PR. In conclusion, ifosfamide, as given, is associated with unacceptable toxicity and insufficient symptomatic efficacy for use as a palliative treatment in patients with relapsed carcinoma of the cervix.

Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a secreted protein that activates macrophages, neutrophils and T cells, and is implicated in sepsis, adult respiratory distress syndrome and rheumatoid arthritis. The mechanism of MIF function, however, is unknown. The three-dimensional structure of MIF is unlike that of any other cytokine, but bears striking resemblance to three microbial enzymes, two of which possess an N-terminal proline that serves as a catalytic base. Human MIF also possesses an N-terminal proline (Pro-1) that is invariant among all known homologues. Multiple sequence alignment of these MIF homologues reveals additional invariant residues that span the entire polypeptide but are in close proximity to the N-terminal proline in the folded protein. We find that p-hydroxyphenylpyruvate, a catalytic substrate of MIF, binds to the N-terminal region and interacts with Pro-1. Mutation of Pro-1 to a glycine substantially reduces the catalytic and cytokine activity of MIF. We suggest that the underlying biological activity of MIF may be based on an enzymatic reaction. The identification of the active site should facilitate the development of structure-based inhibitors.

Long-term follow-up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer.

To test the antitumor effect of gonadotrophin-releasing hormone (GnRH) analogs, 32 consecutive patients with recurrent endometrial cancer that had progressed through conventional treatments were entered into an open observational trial of treatment with this class of compounds. Patients recruited had progressive, symptomatic, and measurable disease. Treatment was with monthly subcutaneous injections of GnRH analog. Measurements of gonadotrophins, sex hormones, and tumor dimensions were made together with repeat biopsy when possible to assess response to treatment. An objective response was seen in nine patients (28%, 95% CI 13-43%). Responses were seen within the first 2 months of treatment and included pelvic as well as distant sites of recurrence. Significantly greater response rates were seen in previously irradiated sites when compared with nonirradiated sites of recurrence (0.01 > P > 0.001). There was no significant difference between the response in patients with G3 lesions compared with patients with G1/G2 lesions (P > 0.5). Response did not correlate with previous progestogen exposure. No evidence of disease flare or drug toxicity was observed. GnRH analogs have a significant and durable antitumor effect in recurrent endometrial cancer which warrants further examination in comparison with progestogens.

Incidence and possible aetiological factors in the development of pelvic insufficiency fractures following radical radiotherapy.

Five patients out of a total of 183 treated with radical radiotherapy for carcinoma of cervix at The Royal Marsden Hospital from 1991 to 1994 inclusive have developed severe pelvic fractures. Two patients had rheumatoid arthritis, one of whom died as a result of the radiation induced damage. This patient developed radiological evidence of radionecrosis within 1 month of completing radiotherapy. There are very few reports in the literature of such a rapid onset. We suggest that the presence of a connective tissue disorder in a patient with other risk factors such as steroid use, old age and osteopenia should alert the clinician to the risk of radionecrosis following radical irradiation.

Computerized axial tomographic scan measurements as prognostic indicators in patients with cervical carcinoma.

This retrospective study of 56 patients with carcinoma of the uterine cervix treated with radical radiotherapy at the Royal Marsden Hospital, London, examined whether simple measurements of maximum tumour dimension from computerized axial tomographic (CT) scans have any prognostic significance. Our results indicate that tumour depth (i.e. maximum antero-posterior dimension) of 4 cm or more is associated with a statistically significant increased relative risk of death of 2.4 (95% CI 1.1-5.5; p = 0.045), as compared with tumours with a depth of less than 4 cm. In addition, there was a clear correlation between tumour depth and lymph node involvement (r = 0.36; p < 0.01), and tumour depth and width (r = 0.70; p < 0.005). We suggest that a measurement of maximum tumour depth from the staging CT scan in these patients provides valuable additional information about likely occult lymph node metastases and prognosis, over and above that suggested by the FIGO staging system alone.

A randomized cross-over study of the efficacy of codeine phosphate versus Ispaghulahusk in patients with gynaecological cancer experiencing diarrhoea during pelvic radiotherapy.

Diarrhoea is the commonest acute complication during radiotherapy treatment to the pelvis. Codeine phosphate and a low residue diet is the standard therapy for radiation-induced diarrhoea at The Royal Marsden NHS Trust. The hypothesis put forward was that Ispaghulahusk and codeine phosphate were equally effective in the treatment of diarrhoea during radiotherapy. Participants in the study were female patients who had experienced change of bowel habit whilst receiving radiotherapy for their gynaecological cancer. Quantitative data was collected from patient diaries and treatment flow-sheets. Ten patients were randomized into the trial, five to codeine phosphate, and five to Ispaghulahusk. Continuing the trial was questioned after 10 patients had been treated. All five patients in the codeine phosphate arm received adequate control, while the five patients allocated to the Ispaghulahusk arm were all crossed-over to codeine phosphate with resolution of their diarrhoea. The results show that Ispaghulahusk, whilst not totally ineffective at controlling diarrhoea, was significantly less effective than codeine phosphate. Our conclusion is that there is insufficient reason to change to a less effective and less palatable preparation for the control of radiation-induced diarrhoea.

Results of a questionnaire regarding the practice of radiotherapy for carcinoma of the cervix in the UK.

A questionnaire was sent to 50 departments of clinical oncology in the UK in September 1991. The aim was to determine the range of external beam and brachytherapy techniques employed at that time in the radical treatment of carcinoma of the cervix. Replies were received from 35 centres. This paper summarizes the preliminary findings of the study. Low dose rate (LDR) brachytherapy techniques predominated (34/35 = 97%) but 41% of departments (13/32) had future plans for the use of high dose rate (HDR) equipment. For low bulk (Stage I-II) carcinoma of the cervix, there was no detectable association between the total brachytherapy dose prescribed and the brachytherapy dose rate. In bulky (Stage I-II) carcinoma of the cervix treated by initial open teletherapy (without shielding), there was a statistically significant reduction in the prescribed brachytherapy dose with increasing dose rate. There was considerable variation between centres in the measurement or estimation of normal tissue doses during brachytherapy. The range of techniques used and the variation in expected complication rates should be closely monitored via medical audit and a further follow-up questionnaire may reveal important changes.

Is there still a role for lymphography in the management of early stage carcinoma of the cervix?

The value of lymphography in the management of carcinoma of the cervix is controversial and in many institutions has ceased to be used as part of routine staging. We present the results of 103 patients with carcinoma of the cervix treated by radical radiotherapy alone at the Royal Marsden Hospital between 1984 and 1990 all of whom had a staging lymphogram and computed tomography (CT) of the abdomen and pelvis as part of their routine staging prior to therapy. Our results show that 72 patients (70%) had no involved nodes detected on either CT or lymphography (LG--ve/CT--ve) while 16 patients (15.5%) were thought to have involved lymph nodes on lymphography alone but not on CT (LG+ve/CT-ve). The remaining 15 cases (14.5%) had involved lymph nodes on both CT and lymphography (LG+ve/CT+ve). There were no patients shown to have involved lymph nodes on CT with a negative lymphogram. Survival analysis on these three groups showed that patients in the LG+ve/CT+ve group did worse than the other two groups with only a 28% 5 year survival compared with 60% (LG-ve/CT-ve group) and 64% (LG+ve/CT-ve group) (p < 0.1). This effect of lymph node involvement disappeared in a multivariate analysis using Cox regression when stage came out as the strongest factor affecting survival. After controlling for stage, a further analysis of patients with only stage I and II disease has shown that patients who were LG+ve/CT+ve still did significantly (p < 0.05) worse (30% 5 year survival) than the other two groups: LG-ve/CT-ve group altered clinical management in 5/6 patients with stage I or IIA disease who avoided radical surgery and who were given a parametrial boost to the site of lymph node involvement. The possible benefit of this additional treatment to explain the higher survival rate of patients in the LG+ve/CT-ve group is discussed further. We conclude that lymphography still has a limited role to play in patients with early stage disease (I or IIA) who do not appear to have involved lymph nodes on CT scanning.

Relationship of computed tomography tumour volume to patient survival in carcinoma of the cervix treated by radical radiotherapy.

In this retrospective study tumour volume was calculated by two different methods from the staging computed tomographic scans obtained in 1987 of 20 patients with carcinoma of the cervix. All patients underwent treatment by radical radiotherapy and the survival figures at 5 years were analysed. The aim was to identify the nature of the relationship between the true tumour volume and tumour volume obtained by measuring the maximum dimensions in each plane ("cuboid" volume). Significant correlation between the product of height x width x depth and true tumour volume was demonstrated (r = 0.983). A multivariate analysis of survival demonstrated a significantly increased relative risk for positive nodes (p < 0.03) and tumour depth > 3.8 cm (p < 0.04) or tumour width > 5.0 cm (p < 0.03). A significant difference (p < 0.02) between the median tumour volumes for early and late stage disease was present irrespective of the method used to calculate tumour volume. This study demonstrates that cuboid tumour volume can be a good reflection of the true volume; in addition, positive nodes, tumour depth and tumour width are significant determinants of survival.

A randomised study of carboplatin vs sequential ifosfamide/carboplatin for patients with FIGO stage III epithelial ovarian carcinoma. The London Gynaecologic Oncology Group.

In a study designed to compare response rates of patients with stage III epithelial ovarian carcinoma to ifosfamide and carboplatin, 152 patients were randomised to receive either sequential therapy with three cycles of ifosfamide followed by three cycles of carboplatin, or to six cycles of single agent carboplatin. Ifosfamide was given every 3 weeks in a dose of 5 gm m-2 as a 24 h infusion with mesna, 1 gm m-2 by i.v. bolus prior to ifosfamide, 3 gm m-2 with ifosfamide, and 1 gm m-2 as an 8 h infusion after ifosfamide. Carboplatin was given in a dose of 400 mg m-2 by short i.v. infusion every 4 weeks. Sixty-eight evaluable patients were randomised to sequential ifosfamide/carboplatin, and 67 to single agent carboplatin. Median follow-up is 36 months (range 5.5-82.3). After three cycles of treatment two patients in the ifosfamide/carboplatin arm achieved complete remission (CR), and 12 partial remission (PR) for an overall response rate of 29%, whereas in the carboplatin arm ten patients achieved CR, and 23 PR, for an overall response rate of 63% (P = 0.0008). Seven of 15 patients with progressive disease, and nine of 20 patients with stable disease at the initial response evaluation, following three cycles of ifosfamide, subsequently responded to carboplatin therapy so that the final response rate to the complete regimen was 65% for the ifosfamide/carboplatin arm, compared to 71% for the carboplatin arm (NS). For the ifosfamide/carboplatin arm, median recurrence free survival and overall survival were 14.1 months and 18.7 months. Corresponding figures for the carboplatin arm were 14.5 months and 21.5 months (NS). Both treatments were generally well tolerated. However 47% of patients in the ifosfamide/carboplatin arm developed alopecia sufficient to require a wig, compared to only 2% in the carboplatin arm. Ifosfamide is clearly less effective, and more toxic than carboplatin. Ifosfamide failures can however be effectively salvaged by subsequent carboplatin treatment. Ifosfamide cannot be recommended for single agent therapy in ovarian carcinoma, however the combination of carboplatin plus ifosfamide might be a suitable treatment to be tested in a future randomised study against carboplatin alone.

Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings.

We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.

NMR and computational evidence that high-affinity bradykinin receptor antagonists adopt C-terminal beta-turns.

Three tetrapeptides were prepared, each corresponding to the four C-terminal amino acid residues of highly potent, second-generation bradykinin receptor antagonists. The tetrapeptides are (IA) Ser-D-Phe-Oic-Arg, (IIA) Ser-D-Tic-Oic-Arg, and (IIIA) Ser-D-Hype(trans-propyl)-Oic-Arg. Solution conformations for each were determined by incorporating interproton distance restraints, determined by 2D NMR experiments performed in water at neutral pH, into a series of distance geometry/simulated annealing model building calculations. Similarly, systematic conformational analyses were performed for each using molecular mechanics calculations. Both the NMR-derived structures, as well as the calculated structures, are shown to adopt a beta-turn as the primary conformation. Excellent agreement between the predicted structures and the NMR-derived structures is demonstrated. Aside from being the first examples of linear tetrapeptides reported to be ordered in aqueous solvent, the results presented support the hypothesis that high-affinity bradykinin receptor antagonists must adopt C-terminal beta-turn conformations.